COPENHAGEN -- Patients with aggressive forms of metastatic renal cell carcinoma (RCC) benefited more from treatment with cabozantinib (Cometriq) than with sunitinib (Sutent), according to a study reported here.

Progression-free survival in intermediate/poor risk mRCC increased by almost 3 months to 8.2 months with cabozantinib, and more than twice as many patients had objective responses. Sunitinib performed in accordance with historical results in intermediate/high-risk mRCC, as treatment resulted in a median PFS of 5.6 months.

"Sunitinib is a standard-of-care therapy in first-line metastatic renal cell carcinoma, associated with a median progression-free survival of 8 to 11 months, according to standard first-line trials of VEGF receptor tyrosine kinase inhibitors," said Choueiri. "Patients with intermediate and poor risk disease have a worse prognosis.

"Cabozantinib improved progression-free survival and objective response rate compared with sunitinib in intermediate and poor-risk patients and, as a result, represents a potential first-line option for patients with advanced RCC."

Sunitinib has been a long-time standard as initial targeted therapy for mRCC, and cabozantinib emerged recently as an appropriate second-line option after disease progression or failure with sunitinib, said ESMO clinical expert Bernard Escudier, MD, of Gustave Roussy Institute in Villejuif, France.

"Obviously, this study will raise a lot of questions, such as whether these results are expandable to all metastatic renal cell carcinoma patients, including the good prognosis group; whether cabozantinib should become a new standard of care in the first-line setting; and how we should interpret all the ongoing phase III first-line studies which selected sunitinib as the control arm," said Escudier.

"While more mature data and additional studies using cabozantinib in the first-line setting will be required, this study creates a lot of new expectations for the treatment of metastatic renal cell carcinoma."

Cabozantinib is a multitargeted tyrosine kinase inhibitor, with activity against MET, AXL, and VEGF receptors. The agent received FDA approval earlier this year for previously treated advanced RCC.

Sunitinib has approval as initial targeted therapy for mRCC, but patients with intermediate- and poor-risk disease historically have fared worse with whatever therapy used, as compared with patients with standard-risk disease. Choueiri reported findings from the randomized phase II CABOSUN trial to determine whether cabozantinib improved outcomes in intermediate/high-risk mRCC as compared with sunitinib.

"Previous studies metastatic RCC have included patients in all risk categories," Choueiri told MedPage Today. "CABOSUN was unique in that we limited enrollment to patients with intermediate- and poor-risk clinical and disease characteristics. We included no patients who had a favorable prognosis. Intermediate and poor risk are associated with worse performance status and presence of bone metastases."

Patients were randomized to the two different tyrosine kinase inhibitors and treated until disease progression, death, or development of unacceptable adverse events. The primary endpoint was PFS, and secondary endpoints included overall survival, investigator-assessed objective response rate, and safety.

The primary analysis included 157 randomized patients. The data showed a median PFS of 8.2 months with cabozantinib and 5.6 months with sunitinib. The 2.-6-month difference represented a 31% reduction in the hazard for progression or death in favor of cabozantinib (95% CI 0.48-0.99, P=0.012).

Choueiri said the difference did not result from subpar performance by sunitinib, as historical results from cohort studies and clinical trials demonstrated a PFS of about 5.6 months for patients with intermediate- and poor-risk mRCC.

Analysis of objective response demonstrated a clear advantage for cabozantinib. The overall response rates were 46% with cabozantinib and 18% with sunitinib.

Overall survival data remained immature, but a preliminary analysis yielded an advantage for the cabozantinib-treated patients, who had a median survival of 30.3 months versus 21.8 months with sunitinib (HR 0.80, 95% CI 0.50-1.26), which was not statistically significant.

Patients in the cabozantinib group remained on treatment longer (median of five 6-week cycles versus two in the sunitinib group). Nonetheless, adverse event rates were similar between groups.

About two-thirds of patients in each group had grade 3/4 adverse events. The most common grade 3/4 adverse events with cabozantinib were hypertension (28%), diarrhea (10%), hand-foot syndrome (8%), and fatigue. The most common grade 3/4 adverse events with sunitinib were hypertension (22%), fatigue (15%), diarrhea (11%), thrombocytopenia (11%), and oral mucositis (6%).

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